Novel Inhibitors of Staphylococcus aureus Virulence Gene Expression and Biofilm Formation

Abstract

Staphylococcus aureus is a major human pathogen and one of the more prominent pathogens causing biofilm related infections in clinic. Antibiotic resistance in S. aureus such as methicillin resistance is approaching an epidemic level. Antibiotic resistance is widespread among major human pathogens and poses a serious problem for public health. Conventional antibiotics are either bacteriostatic or bacteriocidal, leading to strong selection for antibiotic resistant pathogens. An alternative approach of inhibiting pathogen virulence without inhibiting bacterial growth may minimize the selection pressure for resistance. In previous studies, we identified a chemical series of low molecular weight compounds capable of inhibiting group A streptococcus virulence following this alternative anti-microbial approach. In the current study, we demonstrated that two analogs of this class of novel anti-virulence compounds also inhibited virulence gene expression of S. aureus and exhibited an inhibitory effect on S. aureus biofilm formation. This class of anti-virulence compounds could be a starting point for development of novel anti-microbial agents against S. aureus.

Major components of orange oil inhibit Staphylococcus aureus growth and biofilm formation, and alter its virulence factors

“…Methods were adapted from literature previously described by Karaolis et al (2005), O'Toole (2011) and Ma et al (2012). S. aureus was adjusted to 10 8 c.f.u.…”

Role of Extracellular Proteases in Biofilm Disruption of Gram Positive Bacteria with Special Emphasis on Staphylococcus aureus Biofilms

“…The initial belief that, almost all microbial biofilms have polysaccharides as the major 'sticking' substance has been altered, with increasing highlights the role proteases as enzymes with potential to disassemble already well established biofilms or prevent initial attachment itself that is essential for biofilm formation [41,42]. This review highlighted the role of self-produced extracellular proteases of S. aureus in biofilm dispersal as well as role of commercially available broad spectrum proteases in biofilm disruption of other Gram positive bacterium.…”

Chemical Biology Applied to the Study of Bacterial Pathogens

“…Another analog, CCG-203592, inhibited SK at a level 35-fold greater than that seen with CCG-2979 (8). Subsequent work led to the observation that this and other analogs are also effective against another Gram-positive pathogen, Staphylococcus aureus.…”

“…Furthermore, GAS treated with 5 or 50 M CCG-2979 were more susceptible to phagocytosis by host cells. A series of structural analogs of CCG-2979 was generated, and structure-activity relationship (SAR) studies were performed (8,60). The effect of one chemical analog, CCG-102487, on global gene expression was examined by microarray analysis, which demonstrated that expression of 29% of GAS genes in addition to that of ska was altered, with the vast majority of them being reduced in expression.…”

“…aureus is a major public health problem due in part to its ability to form biofilms on implantable devices (61). Biofilm formation of three different biofilm-producing S. aureus strains was reduced in the presence of 50 M CCG-203592, both in laboratory microtiter plates and on silicone, the most common surface used for implantable medical devices (8). Thus, this class of compounds may have therapeutic applications against different traits expressed by two classes of important human pathogens, GAS and S. aureus, making them interesting therapeutic leads.…”